New compounds, their preparation and use

ABSTRACT

The present invention relates to compounds of the general formula (I)  
                 
 
     The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

FIELD OF INVENTION

[0001] The present invention relates to novel compounds, pharmaceuticalcompositions containing them, methods for preparing the compounds andtheir use as medicaments. More specifically, compounds of the inventioncan be utilised in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR).

BACKGROUND OF THE INVENTION

[0002] Coronary artery disease (CAD) is the major cause of death in Type2 diabetic and metabolic syndrome patients (i.e. patients that fallwithin the ‘deadly quartet’ category of impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

[0003] The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

[0004] Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

[0005] PPARα is involved in stimulating β-oxidation of fatty acids. Inrodents, a PPARα-mediated change in the expression of genes involved infatty acid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

[0006] A number of compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia(U.S. Pat. No. 5,306,726, PCT Publications nos. WO 91/19702, WO95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO97/25042, WO 95/17394, WO 99/08501, WO 99/19313 and WO 99/16758).

SUMMARY OF THE INVENTION

[0007] Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia. The clinical activity of fibrates andthiazolidinediones indicates that research for compounds displayingcombined PPARα and PPARγ activation should lead to the discovery ofefficacious glucose and triglyceride lowering drugs that have greatpotential in the treatment of Type 2 diabetes and the metabolic syndrome(i.e. impaired glucose tolerance, insulin resistance,hypertriglyceridaemia and/or obesity).

DETAILED DESCRIPTION OF THE INVENTION

[0008] Accordingly, the present invention relates to compounds of thegeneral formula (I):

[0009] wherein ring A and ring B, fused to the ring containing X and T,independently of each other represents a 5-6 membered cyclic ring,optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro, cyano, formyl, or C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, C₁₋₁₂-alkoxy, aryloxy, arylalkyl, arylalkoxy,heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy,hydroxyC₁₋₁₂-alkyl, amino, acylamino, C₁₋₁₂-alkyl-amino, arylamino,arylalkylamino, amino-C₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl,aryloxycarbonyl, arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl,aryloxyC₁₋₁₂-alkyl, arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio,thioC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, bicycloalkyl, (C₃₋₆-cycloalkyl)C₁₋₆-alkyl,C₁₋₆-dialkylamino, C₁₋₆-alkylsulfonyl, C₁₋₆-monoalkylaminosulfonyl,C₁₋₆-dialkylaminosulfonyl, arylthio, arylsulfonyl,C₁₋₆-monoalkylaminocarbonyl, C₁₋₆-dialkylaminocarbonyl, —COR⁶ or —SO₂R⁷,wherein R⁶ and R⁷ independently of each other are selected from hydroxy,halogen, perhalomethyl, C₁₋₆-alkoxy or amino optionally substituted withone or more C₁₆-alkyl or perhalomethyl; or aryl, wherein the aryloptionally can be substituted with one or more halogen, perhalomethyl,hydroxy, nitro or cyano; or heteroaryl, wherein the heteroaryloptionally can be substituted with halogen, amino hydroxy, C₁₋₆-alkyl orC₁₋₆-alkoxy; or heterocyclyl, wherein the heterocyclyl optionally can besubstituted with halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy;

[0010] X is a valence bond, —(CHR⁸)—, —(CHR⁸)—CH₂—, —CH═CH—, —O—(CHR⁸)—,—S—(CHR⁸)—, —(NR⁸)—CH₂—, —(CHR⁸)—CH═CH—, —(CHR⁸)—CH₂—CH₂—, —(C═O)—,—O—CH₂—O—, —(NR⁸)—S(O₂)—, —CH═(CR⁸)—, —(CO)—(CHR⁸)—, —CH₂—(SO)—, —(SO)—,—(SO₂)—, —CH₂—(SO₂)—, —CH₂—O—CH₂—, wherein R⁸ is hydrogen, halogen,hydroxy, nitro, cyano, formyl, C₁₋₁₂-alkyl, C₁₋₁₂-alkoxy, aryl, aryloxy,arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, C₁₋₁₂-alkyl-amino, arylamino, arylalkylamino,aminoC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl, aryloxycarbonyl,arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl, aryloxyC₁₋₁₂-alkyl,arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio, thioC₁₋₁₂-alkyl,C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, —COR⁹ or —SO₂R¹⁰, wherein R⁹ and R¹⁰independently of each other are selected from hydroxy, halogen,C₁₋₆-alkoxy, amino optionally substituted with one or more C₁₋₆-alkyl,perhalomethyl or aryl;

[0011] T is N or CR¹⁴, wherein R¹⁴ is hydrogen, C₁₋₁₂-alkoxy,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl orarylalkyl;

[0012] Y is C, O, S, CO, SO, SO₂ or NR¹¹, wherein R¹¹ is hydrogen,C₁₋₆-alkyl;

[0013] k is 1 or 2;

[0014]

represents a single or a double bond;

[0015] Ar represents arylene, heteroarylene, or a divalent heterocyclicgroup each of which can optionally be substituted with one or morehalogen, C₁₋₆-alkyl, amino, hydroxy, C₁₋₆-alkoxy or aryl;

[0016] R¹ represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl;optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro or cyano;

[0017] R² represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl;optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro or cyano; or R² forms a bond together with R³;

[0018] R³ represents hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, acyl orarylalkyl; optionally substituted with one or more halogen,perhalomethyl, hydroxy, nitro or cyano; or R³ forms a bond together withR²;

[0019] R⁴ represents hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, arylalkyl, heterocyclyl, heteroarylor heteroarylalkyl groups; optionally substituted with one or morehalogen, perhalomethyl, hydroxy, nitro or cyano;

[0020] R⁵ represents hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, arylalkyl, heterocyclyl, heteroarylor heteroarylalkyl groups; optionally substituted with one or morehalogen, perhalomethyl, hydroxy, nitro or cyano;

[0021] Z represents oxygen or NR¹², wherein R¹² represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Z isNR¹², R⁴ and R¹² may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆-alkyl;

[0022] Q represents oxygen or NR¹³, wherein R¹³ represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Q isNR¹³, R⁵ and R¹³ may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆-alkyl;

[0023] n is an integer ranging from 0 to 3;

[0024] m is an integer ranging from 0 to 1;

[0025] p is an integer ranging from 0 to 1;

[0026] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0027] In one embodiment, the present invention is concerned withcompounds of formula I wherein ring A and ring B, fused to the ringcontaining X and T independently of each other represents a 5-6 memberedcyclic ring, optionally substituted with halogen, C₁₋₆-alkyl or aryl,wherein the aryl can be substituted with one or more halogen orC₁₋₆-alkyl; or heterocyclyl, wherein the heterocyclyl can be substitutedwith C₁₋₆-alkyl.

[0028] In another embodiment, the present invention is concerned withcompounds of formula I wherein ring A and ring B, fused to the ringcontaining X and T independently of each other represents a 5-6 memberedcyclic ring, optionally substituted with heterocyclyl, wherein theheterocyclyl can be substituted with C₁₋₆-alkyl.

[0029] In another embodiment, the present invention is concerned withcompounds of formula I wherein ring A and ring B, fused to the ringcontaining X and T independently of each other represents aryl orpyridyl, optionally substituted with oxadiazolyl, wherein theoxadiazolyl can be substituted with C₁₄-alkyl.

[0030] In another embodiment, the present invention is concerned withcompounds of formula I wherein X is a valence bond, —(CHR⁸)—,—(CHR⁸)—CH₂—, —O—(CHR⁸)— or —S—(CHR⁸)—, wherein R⁸ is hydrogen.

[0031] In another embodiment, the present invention is concerned withcompounds of formula I wherein X is a valence bond, —(CHR⁸)—CH₂— or—S—(CHR⁸)—, wherein R⁵ is hydrogen.

[0032] In another embodiment, the present invention is concerned withcompounds of formula I wherein T is N or CR¹⁴,wherein R¹⁴ is hydrogen.

[0033] In another embodiment, the present invention is concerned withcompounds of formula I wherein Y is C, O or S.

[0034] In another embodiment, the present invention is concerned withcompounds of formula I wherein k is 2.

[0035] In another embodiment, the present invention is concerned withcompounds of formula I wherein

represents a single bond.

[0036] In another embodiment, the present invention is concerned withcompounds of formula I wherein Ar represents arylene.

[0037] In another embodiment, the present invention is concerned withcompounds of formula I wherein R¹, R² and R³ represents hydrogen.

[0038] In another embodiment, the present invention is concerned withcompounds of formula I wherein R⁴ and R⁵ represents hydrogen or methyl.

[0039] In another embodiment, the present invention is concerned withcompounds of formula I wherein Z and Q represents O.

[0040] In another embodiment, the present invention is concerned withcompounds of formula I wherein n is 1.

[0041] In another embodiment, the present invention is concerned withcompounds of formula I wherein m is 1.

[0042] In another embodiment, the present invention is concerned withcompounds of formula I wherein p is 0.

[0043] In specific embodiments, compounds of the invention are:

[0044] 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid dimethylester,

[0045] 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid,

[0046]2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonicacid dimethyl ester,

[0047]2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-α-carbolin-9-yl]-ethoxy}-benzyl)-malonicacid ester dimethyl; or a salt thereof with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.

[0048] In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

[0049] The term “C_(1-n′)-alkyl” wherein n′ can be from 2 through 12, asused herein, represents a branched or straight or cyclic alkyl grouphaving from one to the specified number of carbon atoms. Examples ofsuch groups include, but are not limited to methyl, ethyl, n-propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andthe like and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl and the like.

[0050] The terms “C_(2-n′)-alkenyl” wherein n′ can be from 3 through 15,as used herein, represents an olefinically unsaturated branched orstraight group having from 2 to the specified number of carbon atoms andat least one double bond. Examples of such groups include, but are notlimited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-proppenyl,1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.

[0051] The terms “C_(2-n′)-alkynyl” wherein n′ can be from 3 through 15,as used herein, represent an unsaturated branched or straight grouphaving from 2 to the specified number of carbon atoms and at least onetriple bond. Examples of such groups include, but are not limited to,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl andthe like.

[0052] The terms “C_(4-n′)-alkenynyl” wherein n′ can be from 5 through15, as used herein, represent an unsaturated branched or straighthydrocarbon group having from 4 to the specified number of carbon atomsand both at least one double bond and at least one triple bond. Examplesof such groups include, but are not limited to, 1-penten-4-yne,3-penten-1-yne, 1,3-hexadiene-5-yne and the like.

[0053] The term “C₁₋₁₂-alkoxy” as used herein, alone or in combinationis intended to include those C₁₋₁₂-alkyl groups of the designated lengthin either a linear or branched or cyclic configuration linked thorugh anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy and the like. Examples of branched alkoxy are isoprpoxy,sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like. Examples ofcyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and the like.

[0054] The term “C₁₋₁₂-alkylthio” as used herein, alone or incombination, refers to a straight or branched or cyclic monovalentsubstituent comprising a C₁₋₁₂-alkyl group linked through a divalentsulfur atom having its free valence bond from the sulfur atom and having1 to 12 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio,pentylthio and the like. Examples of cyclic alkylthio arecyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and thelike.

[0055] The term “C₁₋₁₂-alkylamino” as used herein, alone or incombination, refers to a straight or branched or cyclic monovalentsubstituent comprising a C₁₋₁₂-alkyl group linked through amino having afree valence bond from the nitrogen atom e.g. methylamino, ethylamino,propylamino, butylamino, pentylamino and the like. Examples of cyclicalkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and the like.

[0056] The term “hydroxyC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached a hydroxy group, e.g. hydroxyethyl, 1-hydroxypropyl,2-hydroxypropyl and the like.

[0057] The term “arylamino” as used herein, alone or in combination,refers to an aryl as defined herein linked through amino having a freevalence bond from the nitrogen atom e.g. phenylamino, naphthylamino andthe like.

[0058] The term “arylalkylamino” as used herein, alone or incombination, refers to an arylalkyl as defined herein linked throughamino having a free valence bond from the nitrogen atom e.g.benzylamino, phenethylamino, 3-phenylpropylamino, 1-naphtylmethylamino,2-(1-naphtyl)ethylamino and the like.

[0059] The term “aminoC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached an amino group, e.g. aminoethyl, 1-aminopropyl, 2-aminopropyland the like.

[0060] The term “aryloxycarbonyl” as used herein, alone or incombination, refers to an aryloxy as defined herein linked through acarbonyl having a free valence bond from the carbon atom, e.g.phenoxycarbonyl, 1-naphthyloxycarbonyl or 2-naphthyloxycarbonyl and thelike.

[0061] The term “arylalkoxycarbonyl” as used herein, alone or incombination, refers to an arylalkoxy as defined herein linked through acarbonyl having a free valence bond from the carbon atom, e.g.benzyloxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl,1-naphthylmethoxycarbonyl, 2-(1-naphtyl)ethoxycarbonyl and the like.

[0062] The term “C₁₋₁₂-alkoxyC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached a C₁₋₁₂-alkoxy as defined herein, e.g. methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

[0063] The term “aryloxyC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached an aryloxy as defined herein, e.g. phenoxymethyl,phenoxydodecyl, 1-naphthyloxyethyl, 2-naphthyloxypropyl and the like.

[0064] The term “arylalkoxyC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached an arylalkoxy as defined herein, e.g. benzyloxymethyl,phenethoxydodecyl, 3-phenylpropoxyethyl, 1-naphthylmethoxypropyl,2-(1-naphtyl)ethoxymethyl and the like.

[0065] The term “thioC₁₋₁₂-alkyl” as used herein, alone or incombination, refers to a C₁₋₁₂-alkyl as defined herein whereto isattached a group of formula —SR′″ wherein R′″ is hydrogen, C₁₋₆-alkyl oraryl, e.g. thiomethyl, methylthiomethyl, phenylthioethyl and the like.

[0066] The term “C₁₋₁₂-alkoxycarbonylamino” as used herein, alone or incombination, refers to a C₁₋₁₂-alkoxycarbonyl as defined herein linkedthrough amino having a free valence bond from the nitrogen atom e.g.methoxycarbonylamino, carbethoxyamino, propoxycarbonylamino,isopropoxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylaminoand the like.

[0067] The term “aryloxycarbonylamino” as used herein, alone or incombination, refers to an aryloxycarbonyl as defined herein linkedthrough amino having a free valence bond from the nitrogen atom e.g.phenoxycarbonylamino, 1-naphthyloxycarbonylamino or2-naphthyloxycarbonylamino and the like.

[0068] The term “arylalkoxycarbonylamino” as used herein, alone or incombination, refers to an arylalkoxycarbonyl as defined herein linkedthrough amino having a free valence bond from the nitrogen atom e.g.benzyloxycarbonylamino, phenethoxycarbonylamino,3-phenylpropoxycarbonylamino, 1-naphthylmethoxycarbonylamino,2-(1-naphtyl)ethoxycarbonylamino and the like.

[0069] The term “aryl” is intended to include aromatic rings, such ascarboxylic aromatic rings selected from the group consisting of phenyl,naphthyl, (1-naphtyl or 2-naphtyl) and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy and the like.

[0070] The term “arylene” is intended to include divalent aromaticrings, such as carboxylic aromatic rings selected from the groupconsisting of phenylene, naphthylene and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy and the like.

[0071] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0072] The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl.

[0073] The term “C₁₋₆-dialkylamino” as used herein refers to an aminogroup wherein the two hydrogen atoms independently are substituted witha straight or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms; such as dimethylamino, N-ethyl-N-methylamino,diethylamino, dipropylamino, N-(n-butyl)-N-methylamino,di(n-pentyl)amino and the like.

[0074] The term “acyl” as used herein refers to a monovalent substituentcomprising a C₁₋₆-alkyl group linked through a carbonyl group; such ase.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and thelike.

[0075] The term “acyloxy” as used herein refers to acyl as definedherein linked to an oxygen atom having its free valence bond from theoxygen atom e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,pivaloyloxy, valeryloxy and the like.

[0076] The term “C₁₋₁₂-alkoxycarbonyl” as used herein refers to amonovalent substituent comprising a C₁₋₁₂-alkoxy group linked through acarbonyl group; such as e.g. methoxycarbonyl, carbethoxy,propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl,n-hexoxycarbonyl and the like.

[0077] The term “bicycloalkyl” as used herein refers to a monovalentsubstituent comprising a bicyclic structure made of 6-12 carbon atomssuch as e.g. 2-norbornyl, 7-norbornyl, 2-bicyclo[2.2.2]octyl and9-bicyclo[3.3.1]nonanyl and the like.

[0078] The term “heteroaryl” as used herein, alone or in combination,refers to a monovalent substituent comprising a 5-6 membered monocyclicaromatic system or a 9-10 membered bicyclic aromatic system containingone or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine,pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole,oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline,quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine andthe like.

[0079] The term “heteroarylene” as used herein, alone or in combination,refers to a divalent group comprising a 5-6 membered monocyclic aromaticsystem or a 9-10 membered bicyclic aromatic system containing one ormore heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan,thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine,pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole,benzimidazole, benzofuran, pteridine and purine and the like.

[0080] The term “heteroaryloxy” as used herein, alone or in combination,refers to a heteroaryl as defined herein linked to an oxygen atom havingits free valence bond from the oxygen atom e.g. pyrrole, imidazole,pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine,isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline,isoquinoline, quinazoline, quinoxaline, indole, benzimidazole,benzofuran, pteridine and purine linked to oxygen, and the like.

[0081] The term “arylalkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with an aromatic carbohydride; such as benzyl, phenethyl,3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.

[0082] The term “aryloxy” as used herein refers to phenoxy,1-naphthyloxy, 2-naphthyloxy and the like.

[0083] The term “arylalkoxy” as used herein refers to a C₁₋₆-alkoxygroup substituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy andthe like.

[0084] The term “heteroarylalkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with a heteroaryl group; such as (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.

[0085] The term “heteroarylalkoxy” as used herein refers to aheteroarylalkyl as defined herein linked to an oxygen atom having itsfree valence bond from the oxygen atom, e.g. (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl linked to oxygen, andthe like.

[0086] The term “C₁₋₆-alkylsulfonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-alkyl group linked through asulfonyl group such as e.g. methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl, n-hexylsulfonyl,4-methylpentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl,2,2-dimethylpropylsulfonyl and the like.

[0087] The term “C₁₋₆-monoalkylaminosulfonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-monoalkylamino group linkedthrough a sulfonyl group such as e.g. methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,n-butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl,tert-butylaminosulfonyl, n-pentylaminosulfonyl,2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl,n-hexylaminosulfonyl, 4-methylpentylaminosulfonyl,neopentylaminosulfonyl, n-hexylaminosulfonyl,2,2-dimethylpropylaminosulfonyl and the like.

[0088] The term “C₁₋₆-dialkylaminosulfonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-dialkylamino group linkedthrough a sulfonyl group such as dimethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl,dipropylaminosulfonyl, N-(n-butyl)-N-methylaminosulfonyl,di(n-pentyl)aminosulfonyl and the like.

[0089] The term “acylamino” as used herein refers to an amino groupwherein one of the hydrogen atoms is substituted with an acyl group,such as e.g. acetamido, propionamido, isopropylcarbonylamino and thelike.

[0090] The term “(C₃₋₆-cycloalkyl)C₁₋₆-alkyl” as used herein, alone orin combination, refers to a straight or branched, saturated hydrocarbonchain having 1 to 6 carbon atoms and being monosubstituted with aC₃₋₆-cycloalkyl group, the cycloalkyl group optionally being mono- orpolysubstituted with C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy; suchas e.g. cyclopropylmethyl, (1-methylcyclopropyl)methyl,1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

[0091] The term “arylthio” as used herein, alone or in combination,refers to an aryl group linked through a divalent sulfur atom having itsfree valence bond from the sulfur atom, the aryl group optionally beingmono- or polysubstituted with C₁₋₆-alkyl, halogen, hydroxy orC₁₋₆-alkoxy; e.g. phenylthio, (4-methylphenyl)-thio,(2-chlorophenyl)thio and the like.

[0092] The term “arylsulfonyl” as used herein refers to an aryl grouplinked through a sulfonyl group, the aryl group optionally being mono-or polysubstituted with C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy;such as e.g. phenylsulfonyl, tosyl and the like.

[0093] The term “C₁₋₆-monoalkylaminocarbonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-monoalkylamino group linkedthrough a carbonyl group such as e.g. methylaminocarbonyl,ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl,n-butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl,tert-butylaminocarbonyl, n-pentylaminocarbonyl,2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl,n-hexylaminocarbonyl, 4-methylpentylaminocarbonyl,neopentylaminocarbonyl, n-hexylaminocarbonyl,2-2-dimethylpropylaminocarbonyl and the like.

[0094] The term “C₁₋₆-dialkylaminocarbonyl” as used herein refers to amonovalent substituent comprising a C₁₋₆-dialkylamino group linkedthrough a carbonyl group such as dimethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl,dipropylaminocarbonyl, N-(n-butyl)-N-methylaminocarbonyl,di(n-pentyl)aminocarbonyl and the like.

[0095] As used herein, the phrase “heterocyclyl” means a monovalentsaturated or unsaturated non aromatic group being monocyclic andcontaining one or more, such as from one to four carbon atom(s), andfrom one to four N, O or S atom(s) or a combination thereof. The phrase“heterocyclyl” includes, but is not limited to, 5-membered heterocycleshaving one hetero atom (e.g. pyrrolidine, pyrroline and the like);5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions(e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine,imidazoline, 4-oxazolone and the like); 5-membered heterocycles havingthree heteroatoms (e.g. tetrahydrofurazan and the like); 5-memberedheterocycles having four heteroatoms; 6-membered heterocycles with oneheteroatom (e.g. piperidine and the like); 6-membered heterocycles withtwo heteroatoms (e.g. piperazine, morpholine and the like); 6-memberedheterocycles with three heteroatoms; and 6-membered heterocycles withfour heteroatoms, and the like.

[0096] As used herein, the phrase “a divalent heterocyclic group” meansa divalent saturated or unsaturated system being monocyclic andcontaining one or more, such as from one to four carbon atom(s), and oneto four N, O or S atom(s) or a combination thereof. The phrase adivalent heterocyclic group includes, but is not limited to, 5-memberedheterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and thelike); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,imidazolidine, imidazoline, 4-oxazolone and the like); 5-memberedheterocycles having three heteroatoms (e.g. tetrahydrofurazan and thelike); 5-membered heterocycles having four heteroatoms; 6-memberedheterocycles with one heteroatom (e.g. piperidine and the like);6-membered heterocycles with two heteroatoms (e.g. piperazine,morpholine and the like); 6-membered heterocycles with threeheteroatoms; and 6-membered heterocycles with four heteroatoms, and thelike.

[0097] As used herein, the phrase “a 5-6 membered cyclic ring” means anunsaturated or saturated or aromatic system containing one or morecarbon atoms and optionally from one to four N, O or S atom(s) or acombination thereof. The phrase “a 5-6 membered cyclic ring” includes,but is not limited to, e.g. cyclopentyl, cyclohexyl, phenyl,cyclohexenyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, 1,3-dioxolanyl, 1,4-dioxolanyl and the like,5-membered heterocycles having one hetero atom (e.g. thiophenes,pyrroles, furans and the like); 5-membered heterocycles having twoheteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles,imidazoles, thiazoles, puirines and the like); 5-membered heterocycleshaving three heteroatoms (e.g. triazoles, thiadiazoles and the like);5-membered heterocycles having four heteroatoms; 6-membered heterocycleswith one heteroatom (e.g. pyridine, quinoline, isoquinoline,phenanthridine, cyclohepta[b]pyridine and the like); 6-memberedheterocycles with two heteroatoms (e.g. pyridazines, cinnolines,phthalazines, pyrazines, pyrimidines, quinazolines, morpholines and thelike); 6-membered heterocycles with three heteroatoms (e.g.1,3,5-triazine and the like); and 6-membered heterocycles with fourheteroatoms and the like.

[0098] Certain of the above defined terms may occur more than once inthe above formula (I), and upon such occurence each term shall bedefined independently of the other.

[0099] The present invention also encompasses pharmaceuticallyacceptable salts of the present compounds. Such salts includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable base addition salts, pharmaceutically acceptable metal salts,ammonium and alkylated ammonium salts. Acid addition salts include saltsof inorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric acids and the like. Representative examplesof suitable organic acids include formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric,pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic,citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium salts and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like.

[0100] The pharmaceutically acceptable salts are prepared by reactingthe compound of formula I with 1 to 4 equivalents of a base such assodium hydroxide, sodium methoxide, sodium hydride, potassiumt-butoxide, calcium hydroxide, magnesium hydroxide and the like, insolvents lilke ether, THF, methanol, t-butanol, dioxane, isopropanol,ethanol etc. Mixture of solvents may be used. Organic bases like lysine,arginine, diethanolamine, choline, guandine and their derivatives etc.may also be used. Alternatively, acid addition salts whereeverapplicable are prepared by treatment with acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid,maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid,palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid,tartaric acid and the like in solvents like ethyl acetate, ether,alcohols, acetone, THF, dioxane etc. Mixture of solvents may also beused.

[0101] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula I may be converted to a1:1 mixture of diastereomeric amides by treating with chiral amines,amino acids, amino alcohols derived from amino acids; conventionalreaction conditions may be employed to convert acid into an amide; thedia-stereomers may be separated either by fractional crystallization orchromatography and the stereoisomers of compound of formula I may beprepared by hydrolysing the pure diastereomeric amide. Variouspolymorphs of compound of general formula I forming part of thisinvention may be prepared by crystallization of compound of formula Iunder different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

[0102] Furthermore, the present compounds of formula I can be utilisedin the treatment and/or prevention of conditions mediated by nuclearreceptors, in particular the Peroxisome Proliferator-Activated Receptors(PPAR).

[0103] The invention also encompasses prodrugs of the present compounds,which on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of the present compounds,which are readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0104] The invention also encompasses active metabolites of the presentcompounds.

[0105] In a further aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes, preferably TypeII diabetes.

[0106] In a still further aspect, the present invention relates to theuse of one or more compounds of the general formula I orpharmaceutically acceptable salts thereof for the preparation of amedicament for the treatment and/or prevention of Type I or Type IIdiabetes, preferably Type II diabetes.

[0107] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of IGT.

[0108] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of Type 2 diabetes.

[0109] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from IGT to Type 2diabetes.

[0110] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

[0111] In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

[0112] In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

[0113] In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

[0114] In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

[0115] In still another aspect, the present compounds may also be usefulfor improving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

[0116] The invention also relates to pharmaceutical compositionscomprising, as an active ingredient, at least one compound of theformula I or any optical or geometric isomer or tautomeric form thereofincluding mixtures of these or a pharmaceutically acceptable saltthereof together with one or more pharmaceutically acceptable carriersor diluents.

[0117] Furthermore, the invention relates to the use of compounds of thegeneral formula I or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

[0118] The present invention also relates to a process for thepreparation of the above said novel compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

[0119] A compound of formula I can be prepared as described below:

[0120] a) Reacting a compound of formula II, wherein A, B, T, X, Y, andp are as defined previously, except that T is not N,

[0121]  through a Wittig process with (PH₃P)₃P(CH₂)_(n+1)OH.Br in thepresence of a suitable base as butyllithium, to give compounds offormula III.

[0122]  wherein A, B, X, Y, T, p and n are defined as previously, exceptthat T is not N. Compounds of formula III may then be reacted underMitsunobu conditions with compounds of formula IV

[0123]  wherein m, R¹, R², R³ are defined as previously and wherein R⁴and R⁵ are defined as previously except H, to give compounds of formulaI, wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³ are defined aspreviously, except that T is not N, and wherein R⁴ and R⁵ are defined aspreviously except H, and wherein m and k is 1 and within the termT═↑(Y)_(p), ══ is defined as a single bond and within the termT══(CH_(k)), ══ is defined as a double bond.

[0124] b) Alternatively a compound of formula V

[0125]  wherein A, B, X, Y, T, p, n, k, and the terms T══(Y)_(p) andT══(CH_(k)) are defined as previously and wherein LG is a suitableleaving group, may be reacted, possible under transition metalcatalysis, with a nucleophilic compound of formula VI

[0126]  wherein Ar, R¹, R², R³ are defined as previously and wherein R⁴and R⁵ are defined as previously except H and wherein “Met” is a metalsuch as zinc or copper, carrying suitable ligands preferentially fromtrifluoro-methanesulfonate or halide to give compounds of formula I,wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³, and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously and wherein R⁴ andR⁵ are defined as previously except H, and wherein m is 0.

[0127] c) Alternatively compounds of formula V wherein A, B, X, Y, T, p,n, and the terms T══(Y)_(p) and T══(CH_(k)) are defined as previouslyand wherein LG is a suitable leaving group (for example halogen,sulfonates, phosphor, hydroxy under Mitsunobu conditions) are reactedwith a compound of VII

[0128]  wherein Ar, Z, Q, R¹, R², R³ are defined as previously andwherein R⁴ and R⁵ are defined as previously except H, to give compoundsof formula 1, wherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³, and theterms T══(Y)_(p) and T══(CH_(k)) are defined as previously and whereinR⁴ and R⁵ are defined as previously except H, and wherein m is 1.

[0129] d) Alternatively a compound of formula VIII

[0130]  wherein A, B, X, Y and p are defined as previously, may bealkylated with a suitable electrophilic reagent such as ethylene oxide,ethyl bromoacetate followed by reduction of the ester to an alcohol,2-bromoethanol or 2-bromoethanol to give a compound of formula X

[0131]  wherein A, B, X, Y, p and n are defined as previously. Thehydroxy group can if needed be converted to a suitable leaving group andreacted with a compound of formula VII, wherein Ar, Z, Q, R¹, R², R³ aredefined as previously and wherein R⁴ and R⁵ are defined as previouslyexcept H, to give compounds of formula I, wherein A, B, X, Y, Ar, Z, Q,p, n, R¹, R² and R³ are defined as previously and within the termsT══(Y)_(p) and T══(CH_(k)), ══ is defined as a singlebond and wherein R⁴and R⁵ are defined as previously except H, and wherein m is 1 and k is 0and wherein T is N.

[0132] e) Alternatively reacting compounds of formula X wherein A, B, X,Y, p and n are defined as previously, with a compound of formula XI

[0133]  wherein Ar is defined as previously, followed by reaction with asuitable Wittig reagent to give a compound of formula XII

[0134]  wherein A, B, X, Y, Ar, Z, Q, p, n, R¹, R², R³, and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously and wherein R⁴ andR⁵ are defined as previously except H. Addition to the double bond ofsuitable reagents give compounds of formula I, wherein A, B, X, Y, Ar,Z, Q, p, n, R¹, R² and R³ are defined as previously and within the termsT══(Y)_(p) and T══(CH_(k)), ══ is defined as a single bond and whereinR⁴ and R⁵ are defined as previously except H, and wherein m is 1 and kis 0 and wherein T is N.

[0135] f) Alternatively compounds of formula I wherein A, B, X, Y, T,Ar, p, n, k, R¹, R², R³, and the terms T══(Y)_(p) and T══(CH_(k)) aredefined as previously and wherein Z and Q is O and wherein R⁴ and R⁵ aredefined as previously except H can either be hydrolysed to thecorresponding acid or be reacted further to give a compound of formula Iwherein A, B, X, Y, T, Ar, Z, Q, p, n, R¹, R², R³, R⁴, R⁵ and the termsT══(Y)_(p) and T══(CH_(k)) are defined as previously.

[0136] Pharmacological Methods

[0137] In Vitro PPAR Alpha and PPAR Gamma Activation Activity.

[0138] Principle: The PPAR gene transcription activation assays werebased on transient transfection into human HEK293 cells of two plasmidsencoding a chimeric test protein and a reporter protein respectively.The chimeric test protein was a fusion of the DNA binding domain (DBD)from the yeast GAL4 transcription factor to the ligand binding domain(LBD) of the human PPAR proteins. The PPAR LBD harbored in addition tothe ligand binding pocket also the native activation domain (activatingfunction 2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will force the fusionprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand, luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

[0139] Methods: Cell culture and transfection: HEK293 cells were grownin DMEM+10% FCS, 1% PS. Cells were seeded in 96-well plates the daybefore transfection to give a confluency of 80% at transfection. 0.8 μgDNA per well was transfected using FuGene transfection reagent accordingto the manufacturers instructions (Boehringer-Mannheim). Cells wereallowed to express protein for 48 h followed by addition of compound.

[0140] Plasmids: Human PPAR α and γ was obtained by PCR amplificationusing cDNA templates from liver, intestine and adipose tissuerespectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. TheLBD from each isoform PPAR was generated by PCR (PPARα: aa 167-C-term;PPARγ: aa 165-C-term) and fused to GAL4-DBD by subcloning fragments inframe into the vector pM1 generating the plasmids pM1αLBD and pM1γLBD.Ensuing fusions were verified by sequencing. The reporter wasconstructed by inserting an oligonucleotide encoding five repeats of theGal4 recognition sequence into the pGL2 vector (Promega).

[0141] Compounds: All compounds were dissolved in DMSO and diluted1:1000 upon addition to the cells. Cells were treated with compound(1:1000 in 200 μl growth medium including delipidated serum) for 24 hfollowed by luciferase assay.

[0142] Luciferase assay: Medium including test compound was aspiratedand 100 PI PBS incl. 1 mM Mg⁺⁺ and Ca⁺⁺ was added to each well. Theluciferase assay was performed using the LucLite kit according to themanufacturers instructions (Packard Instruments). Light emission wasquantified by counting SPC mode on a Packard Instruments top-counter.

[0143] Pharmaceutical Compositions

[0144] In another aspect, the present invention includes within itsscope pharmaceutical compositions comprising, as an active ingredient,at least one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent. The present compoundsmay also be administered in combination with one or more furtherpharmacologically active substances eg. selected from antiobesityagents, antidiabetics, antihypertensive agents, agents for the treatmentand/or prevention of complications resulting from or associated withdiabetes and agents for the treatment and/or prevention of complicationsand disorders resulting from or associated with obesity.

[0145] Thus, in a further aspect of the invention the present compoundsmay be administered in combination with one or more antiobesity agentsor appetite regulating agents.

[0146] Such agents may be selected from the group consisting of CART(cocaine amphetamine regulated transcript) agonists, NPY (neuropeptideY) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

[0147] In one embodiment of the invention the antiobesity agent isleptin. In another embodiment the antiobesity agent is dexamphetamine oramphetamine. In another embodiment the antiobesity agent is fenfluramineor dexfenfluramine. In still another embodiment the antiobesity agent issibutramine. In a further embodiment the antiobesity agent is orlistat.In another embodiment the antiobesity agent is mazindol or phenitermine.Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1)derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S,which is incorporated herein by reference as well as orally activehypoglycaemic agents.

[0148] The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

[0149] In one embodiment of the invention the present compounds areadministered in combination with insulin.

[0150] In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

[0151] In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

[0152] In yet another embodiment the present compounds are administeredin combination with a meglitinide eg. repaglinide.

[0153] In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

[0154] In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

[0155] Furthermore, the present compounds may be administered incombination with nateglinide.

[0156] In still another embodiment the present compounds areadministered in combination with an antihyperlipidemic agent orantilipidemic agent eg. cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol ordextrothyroxine.

[0157] In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

[0158] Furthermore, the present compounds may be administered incombination with one or more antihypertensive agents. Examples ofantihypertensive agents are β-blockers such as alprenolol, atenolol,timolol, pindolol, propranolol and metoprolol, ACE (angiotensinconverting enzyme) inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, quinapril and ramipril, calcium channel blockerssuch as nifedipine, felodipine, nicardipine, isradipine, nimodipine,diltiazem and verapamil, and α-blockers such as doxazosin, urapidil,prazosin and terazosin. Further reference can be made to Remington: TheScience and Practice of Pharmacy, 19^(th) Edition, Gennaro, Ed., MackPublishing Co., Easton, Pa., 1995. It should be understood that anysuitable combination of the compounds according to the invention withone or more of the above-mentioned compounds and optionally one or morefurther pharmacologically active substances are considered to be withinthe scope of the present invention.

[0159] Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: The Science and Practise of Pharmacy, 19^(th) Ed., 1995.The compositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

[0160] Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

[0161] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,which do not deleteriously react with the active compounds.

[0162] The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

[0163] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0164] For nasal administration, the preparation may contain a compoundof formula I dissolved or suspended in a liquid carrier, in particularan aqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

[0165] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

[0166] Tablets, dragees, or capsules having talc and/or a carbohydratecarrier or binder or the like are particularly suitable for oralapplication. Preferable carriers for tablets, dragees, or capsulesinclude lactose, corn starch, and/or potato starch. A syrup or elixircan be used in cases where a sweetened vehicle can be employed.

[0167] A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free 5 mg compound orsalt thereof) Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose,microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mgMagnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 Tapprox. 0.9 mg

[0168] The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

[0169] Such mammals include also animals, both domestic animals, e.g.household pets, and non-domestic animals such as wildlife.

[0170] The compounds of the invention are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per daymay be used. A most preferable dosage is about 0.1 mg to about 70 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a dosage of from about 2 to about 70 mg per day and whenthe condition is under control to reduce the dosage as low as from about0.1 to about 10 mg per day. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

[0171] Generally, the compounds of the present invention are dispensedin unit dosage form comprising from about 0.1 to about 100 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

[0172] Usually, dosage forms suitable for oral, nasal, pulmonary ortransdermal administration comprise from about 0.001 mg to about 100 mg,preferably from about 0.01 mg to about 50 mg of the compounds of formulaI admixed with a pharmaceutically acceptable carrier or diluent.

[0173] Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

[0174] The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

[0175] The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry(MS). NMR shifts (δ) are given in parts per million (ppm) and onlyselected peaks are given. mp is melting point and is given in °C. Columnchromatography was carried out using the technique described by W. C.Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60(Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se. Abbrevations: TLC: thin layer chromatography DMSO:dimethylsulfoxide CDCl₃: deutorated chloroform DMF:N,N-dimethylformamide min: minutes h: hours

Example 1

[0176]

[0177] 2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic Acid DimethylEster

[0178] a) A solution of benzyloxybenzaldehyde (10.6 g, 50.0 mmol) anddimethyl malonate (6.6 g, 50.0 mmol) in benzene (100 mL) containing acatalytic quantity of pipiridinium acetate was refluxed in a Dean-Starktrap for 16 h. After cooling to room temperature, the solution wasconcentrated. The residue was crystallised from ethyl acetate/heptane togive 14.5 g (90%) of 2-(4-benzyloxy-benzylidene)-malonic acid dimethylester: mp 134-135° C. ¹H NMR (300 MHz, CDCl₃): δ 3.82 (s, 3H), 3.86 (s,3H), 5.08 (s, 2H), 6.95 (d, 2H), 7.30-7.45 (m, 7H), 7.70 (s, 1H).

[0179] b) A solution of 2-(4-benzyloxy-benzylidene)-malonic aciddimethyl ester (14.5 g, 44.5 mmol) in methanol (300 mL) was hydrogenatedat 3 atm. in the presence of 5% palladium on charcoal (1.1 g). Thesolution was filtered, and the filtrate evaporated under a vacuum togive 9.2 g (77%) of 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester: ¹HNMR (300 MHz, CDCl₃): δ 3.15 (d, 2H), 3.65 (t, 1H), 3.70 (s, 6H), 6.70(d, 2H), 7.05 (d, 2H).

[0180] c) To a −30° C. cooled solution of 9H-β-carboline (1.0 g, 5.95mmol) in dry THF (30 mL) was added butyllithium (4.12 mL, 6.55 mmol)over a 15 min period. After 30 min at −30° C., the reaction mixture wascooled to −50° C. Ethylene oxide (1.6 mL in a cooled measuring cylinder)was then bubbled into the reaction mixture, in a stream of nitrogen. Thetemperature was slowly raised to −5° C. over a 2 h period, and stirringwas continued for 84 h. The mixture was acidified with 1 N HCl (50 mL)and extracted with diclormethane (2×100 mL). The combined extracts weredried (MgSO₄), and concentrated in vacuo. The product waschromatographed eluted with dichloromethan/methanol (20:1) to give 660mg (53%) of 2-β-carbolin-9-yl-ethanol. ¹H NMR (300 MHz, CDCl₃): δ 3.62(s, 1H), 4.10 (t, 2H), 4.50 (t, 2H), 7.30 (t, 1H), 7.50-7.65 (m, 2H),7.80 (d, 1H), 8.10 (d, 1H), 8.22 (d, 1H), 8.78 (s, 1H).

[0181] d) Under a nitrogen atmosphere, 2-β-carbolin-9-yl-ethanol (212mg, 1.0 mmol), tributylphosphine (303 mg, 1.5 mmol) and2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (238 mg, 1.0 mmol) weresuccessively dissolved in dry benzene (40 mL). Solid azodicarboxylicdipiperidide (ADDP) (378 mg, 1.5 mmol) was added under stirring at 0° C.to the solution. After 10 min, the reaction mixture was brought to roomtemperature and the stirring was continued for 16 h. Heptane (10 mL) wasadded to the reaction mixture and dihydro-ADDP separated out wasfiltered off. After evaporation of the solvent the product waschromatographed eluting with dichloromethane graduated with ethylacetate to give 355 mg (82%) of the title compound; ¹H NMR (300 MHz,CDCl₃): δ 3.10 (d, 2H), 3.55 (t, 1H), 3.65 (s, 6H), 4.35 (t, 2H), 4.75(t, 2H), 6.70 (d, 2H), 7.05 (d, 2H), 7.30 (t, 1H), 7.3-7.63 (m, 2H),7.97 (d, 1H), 8.13 (d, 1H), 8.48 (d, 1H), 9.02 (s, 1H).

Example 2

[0182]

[0183] 2-[4-(2-β-3-Carbolin-9-yl-ethoxy)-benzyl]-malonic Acid,Hydrochloride

[0184] A 1 N aqueous solution of sodium hydroxide (3 mL) was added to asolution of 2-[4-(2-β-carbolin-9-yl-ethoxy)-benzyl]-malonic aciddimethyl ester (185 mg, 0.34 mmol) in a mixture of methanol (3 mL) andtetrahydrofuran (3 mL).The mixture was stirred for 64 h at roomtemperature. After evaporation of organic solvent, water was added, andthe mixture was acidified with 1 N hydrochloric acid. The product wasextracted with a mixture of dichloromethane/isopropanol. The combinedorganic extract was dried (MgSO₄) and concentrated to give the titlecompound (25 mg, 16%); ¹H NMR (300 MHz, CDCl₃): δ 2.99 (d, 2H), 3.47 (t,1H), 4.44 (t, 2H), 5.05 (t, 2H), 6.60 (d, 2H), 3.00 (d, 2H), 7.55 (t,1H), 7.85-8.00 (m, 2H), 8.50 (t, 2H), 8.70 (d, 1H), 9.35 (s, 1H).

Example 3

[0185]

[0186]2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonicAcid Dimethyl Ester

[0187] The title compound was prepared from iminodibenzyl (3.0 g, 15.3mmol), by a sequence analogous to that described in example 1.

[0188]¹H NMR (300 MHz, CDCl₃): δ 3.13 (d, 2H), 3.15 (s, 4H), 3.60 (s,1H), 3.68 (s, 6H), 4.03 (t 2H), 4.17 (t, 2H), 6.70 (d, 2H), 6.88-6.98(m, 2H), 7.00-7.15 (m, 8H).

Example 4

[0189]

[0190]2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-,-carbolin-β-yl]-ethoxy}-benzyl)-malonicAcid Ester Dimethyl

[0191] a) Under a nitrogen atmosphere, 2-benzyloxyethanol (30.4 g, 0.2mol), tributylphosphine (50.4 g, 0.2 mol) and2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (example 1 b) (42.9 g,0.18 mol) were successively dissolved in dry benzene (1.5 L). Solidazodicarboxylic dipiperidide (ADDP) (40.4 g, 0.2 mol) was added understirring at 0° C. to the solution. After 10 min, the reaction mixturewas brought to room temperature and the stirring was continued for 16 h.Heptane (0.5 L) was added and the precipitate was filtered off. Afterevaporation of the solvent the product was chromatographed eluting withheptane graduated with ethyl acetate to give 64.0 g (96%) of2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethyl ester.

[0192]¹H NMR (300 MHz, CDCl₃): δ 3.15 (d, 2H), 3.63 (t, 1H), 3.70 (s,6H), 3.82 (t, 2H), 4.12 (t, 2H), 4.63 (s, 2H), 6.84 (d, 2H), 7.10 (d,2H), 7.30-7.40 (m, 5H).

[0193] b) A solution of 2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic aciddimethyl ester (64.0 g, 172 mmol) in ethyl acetate (700 mL) washydrogenated at 3 atm. in the presence of 10% palladium on charcoal (3.0g). The solution was filtered, and the filtrate evaporated under vacuoto give 2-[4-(2-hydroxy-ethoxy)-benzyl]-malonic acid dimethyl ester.

[0194]¹H NMR (300 MHz, CDCl₃): δ 2.06 (bs, 1H), 3.18 (d, 2H), 3.63 (t,1H), 3.70 (s, 6H), 3.94 (t, 2H), 4.05 (t, 3H), 6.83 (d, 2H), 7.12 (d,2H).

[0195] c) Under a nitrogen atmosphere,2-[4-(2-hydroxy-ethoxy)-benzyl]-malonic acid dimethyl ester (420 mg, 1.5mmol), tributylphosphine (303 mg, 1.5 mmol) and3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-9H-β-carboline (276 mg, 1.0 mmol)were successively dissolved in dry benzene (15 mL). Solidazodicarboxylic dipiperidide (ADDP) (380 mg, 1.5 mmol) was added understirring at 0° C. to the solution. After 10 min, the reaction mixturewas brought to room temperature and the stirring was continued for 16 h.The reaction mixture was cooled on ice again and added another portionof tributylphosphine (303 mg, 1.5 mmol) and ADDP) (380 mg, 1.5 mmol).After 10 min, the reaction mixture was brought to room temperature andthe stirring was continued for another 16 h. The reaction mixture wasconcentrated in vacuo and the residue chromatographed to give 217 mg(40%) of the title compound.

[0196]¹H NMR (300 MHz, CDCl₃): δ 1.48 (d, 6H), 3.10 (d, 2H), 3.20-3.32(m, 1H), 3.57 (t, 1H), 3.65 (s, 6H), 4.40 (t, 2H), 4.85 (t, 2H), 6.68(d, 2H), 7.03 (d, 2H), 7.42 (t, 1H), 7.60-7.72 (m, 2H), 8.24 (d, 1H),8.90 (s, 1H), 9.20 (s, 1H).

1. A compound of formula (I)

wherein ring A and ring B, fused to the ring containing X and T,independently of each other represents a 5-6 membered cyclic ring,optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro, cyano, formyl, or C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, C₁₋₁₂-alkoxy, aryloxy, arylalkyl, arylalkoxy,heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy,hydroxyC₁₋₁₂-alkyl, amino, acylamino, C₁₋₁₂-alkyl-amino, arylamino,arylalkylamino, amino-C₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl,aryloxycarbonyl, arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl,aryloxyC₁₋₁₂-alkyl, arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio,thioC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, bicycloalkyl, (C₃₋₆-cycloalkyl)C₁₋₆-alkyl,C₁₋₆-dialkylamino, C₁₋₆-alkylsulfonyl, C₁₋₆-monoalkylaminosulfonyl,C₁₋₆-dialkylaminosulfonyl, arylthio, arylsulfonyl,C₁₋₆-monoalkylaminocarbonyl, C₁₋₆-dialkylaminocarbonyl, —COR⁶ or —SO₂R⁷,wherein R⁶ and R⁷ independently of each other are selected from hydroxy,halogen, perhalomethyl, C₁₋₆-alkoxy or amino optionally substituted withone or more C₁₋₆-alkyl or perhalomethyl; or aryl, wherein the aryloptionally can be substituted with one or more halogen, perhalomethyl,hydroxy, nitro or cyano; or heteroaryl, wherein the heteroaryloptionally can be substituted with halogen, amino hydroxy, C₁₋₆-alkyl orC₁₋₆-alkoxy; or heterocyclyl, wherein the heterocyclyl optionally can besubstituted with halogen, amino, hydroxy, C₁₋₆-alkyl or C₁₋₆-alkoxy; Xis a valence bond, —(CHR⁸)—, —(CHR⁸)—CH₂—, —CH═CH—, —O—(CHR⁸)—,—S—(CHR⁸)—, —(NR⁸)—CH₂—, —(CHR⁸)—CH═CH—, —(CHR⁸)—CH₂—CH₂—, —(C═O)—,—O—CH₂—O—, —(NR⁸)—S(O₂)—, —CH═(CR⁸)—, —(CO)—(CHR⁸)—, —CH₂—(SO)—, —(SO)—,—(SO₂)—, —CH₂—(SO₂)—, —CH₂—O—CH₂—, wherein R⁸ is hydrogen, halogen,hydroxy, nitro, cyano, formyl, C₁₋₁₂-alkyl, C₁₋₁₂-alkoxy, aryl, aryloxy,arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxyalkyl, amino,acylamino, C₁₋₁₂-alkyl-amino, arylamino, arylalkylamino,aminoC₁₋₁₂-alkyl, C₁₋₁₂-alkoxycarbonyl, aryloxycarbonyl,arylalkoxycarbonyl, C₁₋₁₂-alkoxyC₁₋₁₂-alkyl, aryloxyC₁₋₁₂-alkyl,arylalkoxyC₁₋₁₂-alkyl, C₁₋₁₂-alkylthio, thioC₁₋₁₂-alkyl,C₁₋₁₂-alkoxycarbonylamino, aryloxycarbonylamino,arylalkoxycarbonylamino, —COR⁹ or —SO₂R¹⁰, wherein R⁹ and R¹⁰independently of each other are selected from hydroxy, halogen,C₁₋₆-alkoxy, amino optionally substituted with one or more C₁₋₆-alkyl,perhalomethyl or aryl; T is N or CR¹⁴, wherein R¹⁴ is hydrogen,C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl,C₂₋₁₂-alkynyl, aryl or arylalkyl; Y is C, O, S, CO, SO, SO₂ or NR¹¹,wherein R¹¹ is hydrogen, C₁₋₆-alkyl; k is 1 or 2;

represents a single or a double bond; Ar is arylene, heteroarylene, or adivalent heterocyclic group each of which can optionally be substitutedwith one or more halogen,C₁₋₆-alkyl, amino, hydroxy, C₁₋₆-alkoxy oraryl; R¹ is hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano; R² is hydrogen, hydroxy, halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl,C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl or arylalkyl; optionallysubstituted with one or more halogen, perhalomethyl, hydroxy, nitro orcyano; or R² forms a bond together with R³; R³ is hydrogen, hydroxy,halogen, C₁₋₁₂-alkoxy, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂₋alkenyl,C₂₋₁₂-alkynyl, acyl or arylalkyl; optionally substituted with one ormore halogen, perhalomethyl, hydroxy, nitro or cyano; or R³ forms a bondtogether with R²; R⁴ is hydrogen, C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, arylalkyl, heterocyclyl, heteroarylor heteroarylalkyl groups; optionally substituted with one or morehalogen, perhalomethyl, hydroxy, nitro or cyano; R⁵ is hydrogen,C₁₋₁₂-alkyl, C₄₋₁₂-alkenynyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl,arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl groups;optionally substituted with one or more halogen, perhalomethyl, hydroxy,nitro or cyano; Z is oxygen or NR¹², wherein R¹² represents hydrogenC₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl or arylalkyl groups or when Z isNR¹², R⁴ and R¹² may form a 5 or 6 membered nitrogen containing ring,optionally substituted with one or more C₁₋₆-alkyl; Q is oxygen or NR¹³,wherein R¹³ represents hydrogen C₁₋₁₂-alkyl, aryl, hydroxyC₁₋₁₂-alkyl orarylalkyl groups or when Q is NR¹³, R⁵ and R¹³ may form a 5 or 6membered nitrogen containing ring, optionally substituted with one ormore C₁₋₆-alkyl; n is an integer ranging from 0 to 3; m is an integerranging from 0 to 1; p is an integer ranging from 0 to 1; or a saltthereof with a pharmaceutically acceptable acid or base, or any opticalisomer or mixture of optical isomers, including a racemic mixture, orany tautomeric forms.
 2. The compound of claim 1, wherein ring A andring B, fused to the ring containing X and T independently of each otherrepresents a 5-6 membered cyclic ring, optionally substituted withhalogen, C₁₋₆-alkyl or aryl, wherein the aryl can be substituted withone or more halogen or C₁₋₆-alkyl; or heterocyclyl, wherein theheterocyclyl can be substituted with C₁₋₆-alkyl.
 3. The compound ofclaim 1; wherein ring A and ring B, fused to the ring containing X and Tindependently of each other represents a 5-6 membered cyclic ring,optionally substituted with heterocyclyl, wherein the heterocyclyl canbe substituted with C₁₋₆-alkyl.
 4. The compound of claim 1, wherein ringA and ring B, fused to the ring containing X and T independently of eachother represents aryl or pyridyl, optionally substituted withoxadiazolyl, wherein the oxadiazolyl can be substituted with C₁₋₄-alkyl.5. The compound of claim 1, wherein X is a valence bond, —(CHR⁸)—,—(CHR⁸)—CH₂—, —O—(CHR⁸)— or —S—(CHR⁸)—, wherein R⁸ is hydrogen.
 6. Thecompound of claim 1, wherein X is a valence bond, —(CHR⁸)—CH₂— or—S—(CHR⁸)—, wherein R⁸ is hydrogen.
 7. The compound of claim 1, whereinT is N or CR¹⁴, wherein R¹⁴ is hydrogen.
 8. The compound of claim 1,wherein Y is C, O or S.
 9. The compound of claim 1, wherein k is
 2. 10.The compound of claim 1, wherein

represents a single bond.
 11. The compound of claim 1, wherein Arrepresents arylene.
 12. The compound of claim 1, wherein R¹, R² and R³represents hydrogen.
 13. The compound of claim 1, wherein R⁴ and R⁵represents hydrogen or methyl.
 14. The compound of claim 1, wherein Zand Q represents O.
 15. The compound of claim 1, wherein n is
 1. 16. Thecompound of claim 1, wherein m is
 1. 17. The compound of claim 1,wherein p is
 0. 18. The compound of claim 1 which is2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid dimethyl ester,2-[4-(2-β-Carbolin-9-yl-ethoxy)-benzyl]-malonic acid,2-{4-[2-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-ethoxy]-benzyl}-malonicacid dimethyl ester,2-(4-{2-[3-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-β-carbolin-9-yl]-ethoxy}-benzyl)-malonicacid ester dimethyl, or a salt thereof with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.
 19. Apharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.
 20. The composition of claim 19 in unitdosage form, wherein the compound comprises from about 0.05 to about 100mg, preferably from about 0.1 to about 50 mg.
 21. The pharmaceuticalcomposition of claim 19, for oral, nasal, transdermal, pulmonary, orparenteral administration.
 22. A method for the treatment and/orprevention of conditions mediated by Peroxisome Proliferator-ActivatedReceptors (PPAR), the method comprising administering to a subject inneed thereof an effective amount of a compound according to claim
 1. 23.A method for the treatment of diabetes and/or obesity, the methodcomprising administering to a subject in need thereof an effectiveamount of the compound of claim
 1. 24. The method of claim 23, whereinthe effective amount of the compound is in the range of from about 0.05to about 100 mg per day, preferably from about 0.1 to about 50 mg perday.